This is a VA Career Development Award-2 (CDA-2) application for Dr. Anne Schafer, an endocrinologist and Clinical Research Fellow at the San Francisco Veterans Affairs Medical Center (SFVAMC). Dr. Schafer is establishing herself as a young investigator in patient-oriented clinical research involving the cross-disciplinary fields of obesity, surgical weight loss, and bone metabolism. Obesity is a chronic disease of staggering proportions. Because weight loss through diet and exercise is difficult to attain and maintain, there is escalating interest in surgical weight loss procedures, including Roux-en-Y gastric bypass. Gastric bypass results in marked and durable weight loss and improvement in comorbidities in the general population and in our veteran patients. However, growing evidence indicates that gastric bypass can have negative effects on the skeleton, increasing bone turnover and decreasing bone mineral density (BMD). This is of critical concern given the tremendous impact of osteoporosis and fracture in both men and women. Vitamin D deficiency due to obesity and post-surgical malabsorption may partially explain the decline in bone mass observed after gastric bypass. Other factors are likely involved as well, such as non-vitamin D-mediated calcium malabsorption, signals related to decreased skeletal loading, and changes in fat-secreted hormones or estrogen (due to changes in fat mass and body composition). Dr. Schafer will characterize the effects of gastric bypass on calcium metabolism and the skeleton in a cohort of 60 men and women whose serum 25- hydroxyvitamin D levels are supplemented and maintained at e30 ng/mL. First, she will test the hypothesis that intestinal calcium absorption is impaired following gastric bypass, even in the setting of vitamin D sufficiency. She will do this by measuring fractional calcium absorption pre-operatively and 6 months post- operatively using dual stable isotopic tracers (Aim 1). Then, she will test the hypothesis that gastric bypass results in decreased BMD and in structural changes associated with impaired skeletal strength. She will do this by performing dual-energy X-ray absorptiometry (DXA), quantitative computed tomography (QCT), and high-resolution peripheral QCT (HR-pQCT) pre-operatively and 6 and 12 months post-operatively (Aim 2). QCT and HR-pQCT are advanced imaging techniques that have distinct advantages over standard methods but have not yet been applied to this population. Finally, she will assess body composition changes by anthropometry, DXA, and QCT, and changes in fat-secreted hormones, and she will evaluate the relationship between changes in skeletal parameters and changes in body composition and hormones (Aim 3). This research is expected to impact the clinical care of gastric bypass patients-veterans and non-veterans alike- by helping to shape recommendations about post-operative nutrition, BMD screening, and potential therapy. The proposed research will provide Dr. Schafer with preliminary data for a larger and longer-term prospective study of the skeletal effects of gastric bypass, which she will propose in a Merit Review application before the end of the CDA-2 period. The CDA-2 will also provide Dr. Schafer with crucial training required for her future career as a VA investigator. Specifically, she will acquire training in (1) design and execution of a prospective cohort study; (2) translational tools of metabolic research (e.g., stable isotope methods); (3) use and interpretation of advanced skeletal imaging modalities; and (4) body composition assessment. To achieve her training goals, Dr. Schafer has assembled a mentorship team comprised of experts in endocrinology, study design, surgery, and radiology. Her training will involve a combination of individual tutorials with her mentors and scientific advisors, hands-on experience, and formal coursework. She will complete a Masters Degree in Clinical Research at the University of California, San Francisco (UCSF) and will take advantage of the rich scientific environment at the SFVAMC and UCSF. Dr. Schafer is committed to improving the health care of veterans through clinical research, and the CDA-2 is critical for the attainment of her career objectives. PUBLIC HEALTH RELEVANCE: Obesity is a chronic illness of staggering proportions, and veterans who use the VA for health care have an even higher prevalence of obesity than the general population. Because weight loss through diet and exercise is difficult to attain and maintain, there has been escalating interest in bariatric surgery, including Roux-en-Y gastric bypass. Gastric bypass surgery results in long-term weight loss, dramatic improvement in comorbidities such as diabetes, and decreased mortality. Emerging evidence suggests, however, that gastric bypass may have negative effects on bone health. Because of the serious consequences of osteoporosis and fracture, this is of great concern. The proposed study of the effects of gastric bypass on calcium metabolism and the skeleton will positively impact the clinical care of gastric bypass patients-veterans and non-veterans alike-by their surgeons, primary care providers, and endocrinologists. Further, the knowledge gained will inform future investigation into the relationships between obesity, weight loss, and bone biology.